PulmCrit- Ketamine for alcohol withdrawal?

[PLEASE NOTE: For the most complete & updated material on alcohol withdrawal, please see the Internet Book of Critical Care Chapter on this topic here]

This is part II of an Oktoberfest series on alcohol withdrawal. Part I on phenobarbital is located here.

Recent publications have explored the role of ketamine in alcohol withdrawal. Ketamine undoubtedly has some outstanding properties, which make it well suited for this task:

Proven track record for rapid control of severe agitated delirium.

Doesn’t suppress respiratory drive or airway reflexes.

Powerful anti-epileptic, when given in high enough doses.

Ketamine’s intermediate half-life allows for some titratability. This is a mixed blessing, however, because it means that ongoing therapy requires a continuous infusion.

The challenge is integrating ketamine into a unified, coherent treatment strategy. That requires going beyond the published evidence – hence this bleeding edge advisory on this post.

Part 1: Ketamine infusions

Wong et al. 2014

This is a single-center retrospective cohort study involving 23 patients treated with ketamine infusions for alcohol withdrawal at the University of Pittsburgh ICU between 5/2011-3/2014.1 Most patients were initially admitted to an internal medicine floor and treated with benzodiazepines. Benzodiazepine failure triggered a transfer to the ICU with ketamine initiated as an adjunctive agent. Ketamine infusions were started on average 34 hours after admission, and continued on average for 56 hours. Infusions were dosed at a low rate of ~0.2 mg/kg/hr. Initiation of ketamine correlated with a reduction benzodiazepine dose, which wasn’t statistically significant. About half of the patients received other adjunctive therapy as well (including dexmedetomidine, phenobarbital, haloperidol, and propofol). One-third of patients were intubated for management of alcohol withdrawal, in all cases prior to initiation of ketamine. Ketamine appeared to be safe (one patient became over-sedated but this responded to dose-reduction).

Given the retrospective nature of this study and co-administration of various drugs, it’s impossible to reach any conclusion about the efficacy of ketamine. Ketamine did appear to be safe, which should come as little surprise (the doses used here are within the range of pain-dose ketamine infusions, which are notoriously safe).

Pizon et al 2018

This study was done at the University of Pittsburgh by the same research group.2 A treatment guideline for alcohol withdrawal using adjunctive ketamine was apparently instituted in 3/2011 (involving ketamine infusions at 0.15-0.3 mg/kg/hr with PRN boluses of 0.3 mg/kg). This is a retrospective observational cohort study comparing patients treated before (1/2008-3/2011) versus after (4/2011-1/2015) institution of the guideline. The post-guideline cohort included most of the same patients that were described by Wong et al. above.

Patients treated from 2011-2015 did indeed do better than their counterparts admitted between 2008-2011:

Unfortunately, there are numerous potentially confounding factors:

After the ketamine protocol began, less ill patients may have been admitted to the ICU for the purpose of receiving ketamine (whereas before such patients previously would have been managed with benzodiazepines on the general ward).

Dexmedetomidine use also increased over time, so it’s possible that improvements were related to this.

The study spans eight years, during which critical care overall has improved. Any study of any disease process is likely to show better outcomes in 2015 than in 2008.

Shah et al 2018

This is a single-center retrospective cohort study involving 30 patients treated with ketamine infusions for alcohol withdrawal at Advocate Christ Medical Center in Illinois between 2012-2014.3 Ketamine was used as an adjunctive agent, following the initiation of lorazepam infusions. In most cases patients also received phenobarbital prior to ketamine as well (mean dose 470 mg). On average ketamine was started 41 hours after starting a lorazepam infusion and was continued for 54 hours. The median initial ketamine infusion rate was 0.75 mg/kg/hr and the average maximal rate was 1.6 mg/kg/hr – a much higher dose than the above studies.

Use of ketamine correlated with a reduction in lorazepam infusion rates (shown above). Symptom control was achieved in all patients within an hour. Within 48 hours of starting ketamine, 43% of patients were completely weaned off all infusions. Most of the patients were intubated prior to starting ketamine, but six patients did require intubation following initiation of ketamine infusion. Overall the average ICU length of stay was 8.2 days.

Comments on these studies

Unfortunately, none of these studies proves anything about the use of ketamine infusions for alcohol withdrawal. All studies were retrospective, open-label studies involving simultaneous use of numerous different agents.

Wong 2014 and Pizon 2018 use a very low “pain-dose” ketamine infusion of ~0.2 mg/kg/hr. It’s doubtful whether this dose of ketamine is high enough to do anything for alcohol withdrawal. When used for pain in various patient populations, patients treated with 0.2 mg/kg/hr ketamine usually have no sedative effect from this dose (but rather, solely analgesia). Furthermore, alcoholics tend to be resistant to ketamine (due to up-regulation of NMDA receptors over time).4 Cross-tolerance between alcohol and ketamine has been explored before here. So, this dose is undoubtedly safe, but its efficacy for alcohol withdrawal is unclear. It’s more likely that these infusions were causing clinical improvement simply by treating unrecognized pain (one major cause of refractory agitation).

Shah 2018 use almost 10-fold higher doses, which are more likely to have a real effect. They did observe prompt symptom improvement and rapid weaning off lorazepam infusions, which seem more convincing. However, among the 14 non-intubated patients treated with ketamine, six (43%) eventually required intubation. A major goal when treating alcohol withdrawal is avoidance of intubation, so a 43% intubation rate with ketamine is disappointing. My guess is that intubation was due mostly to the large benzodiazepine doses, but these outcomes are still unimpressive.

Comments on ketamine infusions in general

In my view, the days of treating alcohol withdrawal with a benzodiazepine infusion in the ICU should be over. Likewise, intubating patients purely for alcohol withdrawal should be a rare occurrence. The use of a front-loaded phenobarbital monotherapy strategy seems to have the capacity to greatly reduce the number of patients requiring intubation.5 Most patients may undergo incremental phenobarbital loading over a couple days followed by disposition to the ward. So, for most patients, a prolonged infusion of ketamine should be wholly unnecessary.

Of course, some patients will wind up intubated during alcohol withdrawal (e.g. patients who present with alcohol withdrawal plus pneumonia). A pain-dose ketamine infusion is an excellent choice for such patients. These patients will have some amount of pain (e.g. related to the endotracheal tube), so providing a pain-dose ketamine infusion is a sensible approach purely for analgesia. Perhaps the ketamine infusion will provide some benefit for alcohol withdrawal as well; if so, that’s a bonus. The use of pain-dose ketamine infusions among intubated ICU patients seems extremely promising, as discussed previously here.

The use of dissociative-dose ketamine infusions for analgosedation (e.g. 1.5 mg/kg/hr) is an exciting concept, which might have some role here. However, more research is needed to prove the safety of this strategy. Unlike pain-dose ketamine infusions, there isn’t extensive published experience to support this.

Part 2: Dissociative ketamine boluses

I’ve previously advocated for a phenobarbital monotherapy strategy for alcohol withdrawal. In general, this strategy has worked well, but there is one rare situation where it’s not perfect. That situation is the patient who is profoundly, dangerously agitated due to alcohol withdrawal. Phenobarbital takes a bit of time to obtain from pharmacy. Additionally, it’s unclear how safe it is to push high doses of phenobarbital quickly. So, phenobarbital isn’t well suited for the patient who is actively combative.

Fortunately, this is an uncommon situation. Upon arrival, most alcohol withdrawal patients aren’t dangerously agitated. With phenobarbital therapy, patients are unlikely to deteriorate to this state. However, occasional patients will be encountered who are dangerously agitated due to alcohol withdrawal.

A dissociative ketamine dose (e.g. 2 mg/kg or higher PRN) is well suited to the patient who is profoundly agitated from alcohol withdrawal for a few reasons:

Ketamine will achieve immediate control of symptoms (including any potential danger that the patient may present to themselves and others).

Ketamine use in severe agitated delirium is evidence-based.6

Excited delirium may generate an ongoing vicious cycle of agitation, hyperactivity, hyperthermia, and pain (e.g. from restraints). Dissociative ketamine may potentially break this cycle before it worsens. Often patients may wake up much calmer than they were initially.

Patients will continue to breathe and protect their airway, allowing avoidance of intubation.

Of course, ketamine will only achieve symptom control for 40-60 minutes, after which the patient will start to wake up. Generally, we might consider giving a benzodiazepine to ease the re-emergence experience. But for alcohol withdrawal, we can do better than that by using phenobarbital:

Phenobarbital in a dose of 5-10 mg/kg may be ordered from pharmacy STAT, while the ketamine is being given (using a 10 mg/kg dose for patients who meet criteria for a loading phenobarbital dose). By the time the patient is beginning to wake up from the ketamine, the phenobarbital will be running in (usually infused over 30 minutes). The phenobarbital will prevent re-emergence symptoms, and the patient will wake up with a loading dose of phenobarbital on board.

Of course, a similar strategy could be used with benzodiazepines (dissociate with ketamine, then load with benzodiazepine to prevent re-emergence and treat withdrawal). My preference is phenobarbital rather than benzodiazepines for reasons discussed previously (e.g., unpredictable effect, potentiality of paradoxical reaction, confusing pharmacokinetics when combining benzodiazepines and barbiturates).

There isn’t any evidence supporting this exact strategy. It’s unlikely that high-quality evidence will ever emerge, because this situation is only rarely encountered. I’ve only needed to use it once (worked quite nicely). So, ketamine-phenobarb is merely presented as one possible approach to this problem. If there is a place in alcohol withdrawal where ketamine really shines, it might be in controlling the dangerously agitated patient.

Ketamine has numerous attractive properties which could be helpful in the management of alcohol withdrawal: lack of respiratory suppression, rapid onset, ability to control acute agitation, and anti-seizure activity.

Retrospective observational studies suggest a potential use of ketamine infusion for refractory alcohol withdrawal. More work is needed to clarify the risks vs. benefits of dissociative-dose ketamine infusions. For now, the use of a pain-dose ketamine infusion (0.1-0.3 mg/kg/hr) is a safe and reasonable approach – especially if the patient is intubated or has other sources of pain.

Most patients with alcohol withdrawal will respond very nicely to a phenobarbital monotherapy strategy. Such patients will never have any requirement for any sort of infusion, nor should they have a prolonged ICU stay. So ideally most patients shouldn’t require a ketamine infusion.

Ketamine dissociation may be uniquely suited for immediate behavioral control of a patient who is acutely and dangerously agitated due to alcohol withdrawal. This may be smoothly transitioned to a phenobarbital monotherapy strategy.

related

[PLEASE NOTE: For the most complete & updated material on alcohol withdrawal, please see the Internet Book of Critical Care Chapter on this topic here]

Josh – really interested in the challenge of moving away from BZD. I trained at a very heavy BZD reliant place for etoh w/d. Vast majority never got intubated. Used a lot of phenobarbital as well but learned that I wasn’t using it right most of the time – was waiting until the patient already had large diazepam doses in their system before reaching for it and then expected immediate gains. I’ve started using it earlier but in conjunction with BZDs. My reasoning for this is that phenobarbital takes a bit longer to take action while I can get immediate results with diazepam. The active metabolites in diazepam are beneficial as well.
Bottom line is that I think etoh w/d isn’t a uniform disease where one recommendation holds for all. You gotta add a little of this and a little of that sometimes to see what’s gonna work.